bims-traimu 2023-12-24 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–12–24
fiveteen papers selected by
Yantong Wan, Southern Medical University

HPV vaccines induce trained immunity and modulate pro-inflammatory cytokine expression in response to secondary Toll-like receptor stimulations.
Current Understanding of Bacillus Calmette-Guérin-Mediated Trained Immunity and Its Perspectives for Controlling Intracellular Infections.
Enduring echoes: Post-infectious long-term changes in innate immunity.
Protocol for the induction of innate immune memory in human smooth muscle cells and endothelial cells in vitro.
An overview of the BCG vaccine and its future scope.
Leptospira Lipid A Is a Potent Adjuvant That Induces Sterilizing Immunity against Leptospirosis.
Innate and Adaptive Cell-Mediated Immune Responses to a COVID-19 mRNA Vaccine in Young Children.
Distinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination.
Mobilization of the innate immune response by a specific immunostimulant β-glucan confers resistance to chronic stress-induced depression-like behavior by preventing neuroinflammatory responses.
CD115+ monocytes protect microbially experienced mice against E. coli-induced sepsis.
Glucosylation endows nanoparticles with TLR4 agonist capability to trigger macrophage polarization and augment antitumor immunity.
Low-dose of formalin-inactivated Vibrio alginolyticus protects Crassostrea gigas from secondary infection and confers broad-spectrum Vibrio resistance on offspring.
Staphylococcus aureus suppresses the pentose phosphate pathway in human neutrophils via the adenosine receptor A2aR to enhance intracellular survival.
Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.
Saa3 promotes pro-inflammatory macrophage differentiation and contributes to sepsis-induced AKI.

Microbiol Immunol. 2023 Dec 17.

HPV vaccines induce trained immunity and modulate pro-inflammatory cytokine expression in response to secondary Toll-like receptor stimulations.

Mako Yamaguchi, Yohana S Mtali, Hitomi Sonokawa, Ken Takashima, Yoshimi Fukushima, Takahisa Kouwaki, Hiroyuki Oshiumi.

  Cervical cancer is caused mostly by human papillomavirus (HPV), and several HPV vaccines have been developed to prevent its onset. Vaccines include antigens as well as adjuvants, with adjuvants playing an important role in activating the innate immune responses necessary for inducing adaptive immunological responses. Recent research has shown the presence of trained immunity inside the innate immune system. However, trained immunity conferred by HPV vaccinations is not well understood. In this work, we explored the innate immune responses and trained immunity caused by two HPV vaccines, Cervarix and Gardasil. Cervarix includes monophosphoryl lipid A and an aluminum adjuvant, and it significantly increased the expression of IL-6 and IFN-β mRNAs in RAW264.7 cells. On the contrary, Gardasil, which only includes an aluminum adjuvant, exhibited little cytokine expression but increased the expression of TLRs. Furthermore, Cervarix significantly increased IL-1β secretion from mouse macrophages, while Gardasil only mildly induced IL-1β secretion. Interestingly, initial stimulation with Gardasil enhanced the expression of IL-6 and TNF-α mRNAs upon secondary stimulation with TLR ligands, indicating that Gardasil induced trained immunity in macrophages. Moreover, Gardasil injection into mice resulted in enhanced TNF-α production in sera following secondary TLR stimulation. Our findings suggest that HPV vaccinations have the ability to induce trained immunity that modulate TLR ligand responses.

Keywords:  HPV; inflammation; innate immunity; trained immunity; vaccine

DOI:  https://doi.org/10.1111/1348-0421.13108
Pathogens. 2023 Nov 24. pii: 1386. [Epub ahead of print]12(12):

Current Understanding of Bacillus Calmette-Guérin-Mediated Trained Immunity and Its Perspectives for Controlling Intracellular Infections.

Ana Carolina V S C de Araujo, Fábio Mambelli, Rodrigo O Sanches, Fábio V Marinho, Sergio C Oliveira.

  The bacillus Calmette-Guérin (BCG) is an attenuated bacterium derived from virulent Mycobacterium bovis. It is the only licensed vaccine used for preventing severe forms of tuberculosis in children. Besides its specific effects against tuberculosis, BCG administration is also associated with beneficial non-specific effects (NSEs) following heterologous stimuli in humans and mice. The NSEs from BCG could be related to both adaptive and innate immune responses. The latter is also known as trained immunity (TI), a recently described biological feature of innate cells that enables functional improvement based on metabolic and epigenetic reprogramming. Currently, the mechanisms related to BCG-mediated TI are the focus of intense research, but many gaps are still in need of elucidation. This review discusses the present understanding of TI induced by BCG, exploring signaling pathways that are crucial to a trained phenotype in hematopoietic stem cells and monocytes/macrophages lineage. It focuses on BCG-mediated TI mechanisms, including the metabolic-epigenetic axis and the inflammasome pathway in these cells against intracellular pathogens. Moreover, this study explores the TI in different immune cell types, its ability to protect against various intracellular infections, and the integration of trained innate memory with adaptive memory to shape next-generation vaccines.

Keywords:  BCG; innate memory; intracellular infections; trained immunity

DOI:  https://doi.org/10.3390/pathogens12121386
Eur J Intern Med. 2023 Dec 21. pii: S0953-6205(23)00456-9. [Epub ahead of print]

Enduring echoes: Post-infectious long-term changes in innate immunity.

Elisabeth A Dulfer, Leo A B Joosten, Mihai G Netea.

  Upon encountering pathogens, the immune system typically responds by initiating an acute and self-limiting reaction, with symptoms subsiding after the pathogen has been cleared. However, long-term post-infectious clinical symptoms can manifest months or even years after the initial infection. 'Trained immunity', the functional reprogramming of innate immune cells through epigenetic and metabolic rewiring, has been proposed as a key concept for understanding these long-term effects. Although trained immunity can result in enhanced protection against reinfection with heterologous pathogens, it can also contribute to detrimental outcomes. Persisting and excessive inflammation can cause tissue damage and aggravate immune-mediated conditions and cardiovascular complications. On the other hand, suppression of immune cell effector functions by long-lasting epigenetic changes can result in post-infectious immune paralysis. Distinct stimuli can evoke different trained immunity programs, potentially resulting in different consequences for the host. In this review, we provide an overview of both the adaptive and maladaptive consequences of infectious diseases. We discuss how long-term immune dysregulation in patients can be addressed by tailoring host-directed interventions and identify areas of scientific and therapeutic potential to advance further.

Keywords:  Infectious diseases; Innate immunity; Post-infectious complications; Trained immunity

DOI:  https://doi.org/10.1016/j.ejim.2023.12.020
STAR Protoc. 2023 Dec 19. pii: S2666-1667(23)00743-8. [Epub ahead of print]5(1): 102776

Protocol for the induction of innate immune memory in human smooth muscle cells and endothelial cells in vitro.

Jannik Sonnenberg, Dennis Schwarz, Sina Mm Lagache, Lucia Schnack, Helena Körner, Merle Leffers, Hannah Hardege, Yuanyuan Liu, Holger Reinecke, Hannes M Findeisen, Yahya Sohrabi.

  Non-immune cells, like innate immune cells, can develop a memory-like phenotype in response to priming with microbial compounds or certain metabolites, which enables an enhanced response to a secondary unspecific stimulus. This paper describes a step-by-step protocol for the induction and analysis of trained immunity in human endothelial and smooth muscle cells. We then describe steps for cell culture with cryopreserved vascular cells, subcultivation, and induction of trained immunity. We then provide detailed procedures for downstream analysis using ELISA and qPCR. For complete details on the use and execution of this protocol, please refer to Sohrabi et al. (2020)1 and Shcnack et al.2.

Keywords:  Cell Biology; Immunology; Molecular Biology

DOI:  https://doi.org/10.1016/j.xpro.2023.102776
Indian J Tuberc. 2023 ;pii: S0019-5707(23)00098-7. [Epub ahead of print]70 Suppl 1 S14-S23

An overview of the BCG vaccine and its future scope.

Pallavi Khandelia, Shikha Yadav, Pratichi Singh.

  Despite intense elimination efforts, tuberculosis (TB) still poses a threat to world health, disproportionately affecting less developed and poorer countries. The Bacillus Calmette-Guérin (BCG) vaccine, the only anti-TB authorized vaccine can partially stop TB infection and transmission, however, its effectiveness ranges from 0 to 80%. As a result, there is an urgent need for a more potent TB vaccination given the widespread incidence of the disease. Enhancing BCG's effectiveness is also important due to the lack of other licensed vaccinations. Recently, fascinating research into BCG revaccination techniques by modulating its mode of action i.e., intravenous (IV) BCG delivery has yielded good clinical outcomes showing it still has a place in current vaccination regimens. We must thus go over the recent evidence that suggests trained immunity, and BCG vaccination techniques and describe how the vaccination confers protection against bacteria that cause both TB and non-tuberculosis. This review of the literature offers an updated summary and viewpoints on BCG-based TB immunization regimens (how it affects granulocytes at the epigenetic and hematopoietic stem cell levels which may be related to its efficacy), and also examines how the existing vaccine is being modified to be more effective, which may serve as an inspiration for future studies on the development of TB vaccines.

Keywords:  Immune response; Intravenous; Techniques; Tuberculosis; Vaccine

DOI:  https://doi.org/10.1016/j.ijtb.2023.05.012
Vaccines (Basel). 2023 Dec 06. pii: 1824. [Epub ahead of print]11(12):

Leptospira Lipid A Is a Potent Adjuvant That Induces Sterilizing Immunity against Leptospirosis.

Vivek P Varma, Mohammad Kadivella, Sridhar Kavela, Syed M Faisal.

  Leptospirosis is a globally significant zoonotic disease. The current inactivated vaccine offers protection against specific serovars but does not provide complete immunity. Various surface antigens, such as Leptospira immunoglobulin-like proteins (LigA and LigB), have been identified as potential subunit vaccine candidates. However, these antigens require potent adjuvants for effectiveness. Bacterial lipopolysaccharides (LPSs), including lipid A, are a well-known immunostimulant, and clinical adjuvants often contain monophosphoryl lipid A (MPLA). Being less endotoxic, we investigated the adjuvant properties of lipid A isolated from L. interrogans serovar Pomona (PLA) in activating innate immunity and enhancing antigen-specific adaptive immune responses. PLA activated macrophages to a similar degree as MPLA, albeit at a higher dose, suggesting that it is less potent in stimulation than MPLA. Mice immunized with a variable portion of LigA (LAV) combined with alum and PLA (LAV-alum-PLA) exhibited significantly higher levels of LAV-specific humoral and cellular immune responses compared to alum alone but similar to those induced by alum-MPLA. The adjuvant activity of PLA resembles that of MPLA and is primarily achieved through the increased recruitment, activation, and uptake of antigens by innate immune cells. Furthermore, like MPLA, PLA formulation establishes a long-lasting memory response. Notably, PLA demonstrated superior potency than MPLA formulation and provided sterilizing immunity against the leptospirosis in a hamster model. Overall, our study sheds light on the adjuvant properties of Leptospira lipid A and offers promising avenues for developing LPS-based vaccines against this devastating zoonotic disease.

Keywords:  LigA; MPLA; adjuvant; alum; leptospirosis; lipid A; vaccine

DOI:  https://doi.org/10.3390/vaccines11121824
Open Forum Infect Dis. 2023 Dec;10(12): ofad608

Innate and Adaptive Cell-Mediated Immune Responses to a COVID-19 mRNA Vaccine in Young Children.

Adriana Weinberg, Michael J Johnson, Krystle Garth, Elena W Y Hsieh, Ross Kedl, Daniela Weiskopf, Mattie Cassaday, Cody Rester, Berenice Cabrera-Martinez, Ryan M Baxter, Myron J Levin.

   Background: There is little information on cell-mediated immunity (CMI) to COVID-19 mRNA vaccines in children. We studied adaptive and innate CMI in vaccinated children aged 6 to 60 months.
Methods: Blood obtained from participants in a randomized placebo-controlled trial of an mRNA vaccine before and 1 month after the first dose was used for antibody measurements and CMI (flow cytometry).
Results: We enrolled 29 children with a mean age of 28.5 months (SD, 15.7). Antibody studies revealed that 10 participants were infected with SARS-CoV-2 prevaccination. Ex vivo stimulation of peripheral blood mononuclear cells with SARS-CoV-2 spike peptides showed significant increases pre- to postimmunization of activated conventional CD4+ and γδ T cells, natural killer cells, monocytes, and conventional dendritic cells but not mucosa-associated innate T cells. Conventional T-cell, monocyte, and conventional dendritic cell responses in children were higher immediately after vaccination than after SARS-CoV-2 infection. The fold increase in CMI pre- to postvaccination did not differ between children previously infected with SARS-CoV-2 and those uninfected.
Conclusions: Children aged 6 to 60 months who were vaccinated with a COVID-19 mRNA vaccine developed robust CMI responses, including adaptive and innate immunity.

Keywords:  COVID-19 mRNA vaccines; SARS-CoV-2 infection; cell-mediated immunity; children; trained immunity

DOI:  https://doi.org/10.1093/ofid/ofad608
Nat Commun. 2023 Dec 21. 14(1): 8507

Distinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination.

Richard F Silver, Mei Xia, Chad E Storer, Jessica R Jarvela, Michelle C Moyer, Azra Blazevic, David A Stoeckel, Erin K Rakey, Jan M Tennant, Johannes B Goll, Richard D Head, Daniel F Hoft.

Tuberculosis remains an international health threat partly because of limited protection from pulmonary tuberculosis provided by standard intradermal vaccination with Bacillus of Calmette and Guérin (BCG); this may reflect the inability of intradermal vaccination to optimally induce pulmonary immunity. In contrast, respiratory Mycobacterium tuberculosis infection usually results in the immune-mediated bacillary containment of latent tuberculosis infection (LTBI). Here we present RNA-Seq-based assessments of systemic and pulmonary immune cells from LTBI participants and recipients of intradermal and oral BCG. LTBI individuals uniquely display ongoing immune activation and robust CD4 T cell recall responses in blood and lung. Intradermal BCG is associated with robust systemic immunity but only limited pulmonary immunity. Conversely, oral BCG induces limited systemic immunity but distinct pulmonary responses including enhanced inflammasome activation potentially associated with mucosal-associated invariant T cells. Further, IL-9 is identified as a component of systemic immunity in LTBI and intradermal BCG, and pulmonary immunity following oral BCG.

DOI: https://doi.org/10.1038/s41467-023-44136-8
Int Immunopharmacol. 2023 Dec 19. pii: S1567-5769(23)01732-0. [Epub ahead of print]127 111405

Mobilization of the innate immune response by a specific immunostimulant β-glucan confers resistance to chronic stress-induced depression-like behavior by preventing neuroinflammatory responses.

Jie Ren, Yi Zhang, Hainan Pan, Ruiting Shi, Haojie Zhu, Rongrong Yang, Lin Zhang, Bingran Chen, Tao Zhu, Xu Lu, Chao Huang.

  Pre-stimulation of the innate immune response is an effective strategy to prevent depression-like phenotypes in animals. However, the use of conventional immunostimulants may cause adverse effects. Therefore, the search for agents that stimulate the innate immune response but do not induce a pro-inflammatory response could be a new research direction for the prevention of depression. β-glucan is a polysaccharide from Saccharomyces cerevisiae with unique immunomodulatory activity in microglia without eliciting a pro-inflammatory response that could lead to tissue damage. This suggests that β-glucan may be a suitable drug that can be used to prevent depression-like phenotypes. Our results showed that a single injection of β-glucan 1 day before stress exposure at a dose of 10 or 20 mg/kg, but notat a dose of 5 mg/kg, prevented depression-like behavior in mice treated with chronic unpredictable stress (CUS). This effect of β-glucan disappeared when the time interval between β-glucan and stress was extended from 1 day or 5 days to 10 days, which was rescued by a second injection 10 days after the first injection or by a repeated injection (4×, once daily) 10 days before stress exposure. A single β-glucan injection (20 mg/kg) 1 day before stress exposure prevented the CUS-induced increase in brain pro-inflammatory cytokines, and inhibition of the innate immune response by minocycline (40 mg/kg) abolished the preventive effect of β-glucan on CUS-induced depression-like behaviors and neuroinflammatory responses. These results suggest that β-glucan may prevent chronic stress-induced depression-like phenotypes and neuroinflammatory responses by stimulating the innate immune response.

Keywords:  Innate immunization; Neuroinflammatory response; Prevention; β-glucan

DOI:  https://doi.org/10.1016/j.intimp.2023.111405
Cell Rep. 2023 Nov 28. pii: 113345. [Epub ahead of print]42(11):

CD115+ monocytes protect microbially experienced mice against E. coli-induced sepsis.

Matthew D Martin, Cara Skon-Hegg, Caleb Y Kim, Julie Xu, Tamara A Kucaba, Whitney Swanson, Mark J Pierson, Jesse W Williams, Vladimir P Badovinac, Steven S Shen, Molly A Ingersoll, Thomas S Griffith.

Uropathogenic E. coli (UPEC) is a primary organism responsible for urinary tract infections and a common cause of sepsis. Microbially experienced laboratory mice, generated by cohousing with pet store mice, exhibit increased morbidity and mortality to polymicrobial sepsis or lipopolysaccharide challenge. By contrast, cohoused mice display significant resistance, compared with specific pathogen-free mice, to a monomicrobial sepsis model using UPEC. CD115+ monocytes mediate protection in the cohoused mice, as depletion of these cells leads to increased mortality and UPEC pathogen burden. Further study of the cohoused mice reveals increased TNF-α production by monocytes, a skewing toward Ly6ChiCD115+ "classical" monocytes, and enhanced egress of Ly6ChiCD115+ monocytes from the bone marrow. Analysis of cohoused bone marrow also finds increased frequency and number of myeloid multipotent progenitor cells. These results show that a history of microbial exposure impacts innate immunity in mice, which can have important implications for the preclinical study of sepsis.

DOI: https://doi.org/10.1016/j.celrep.2023.113345
Biomaterials. 2023 Dec 11. pii: S0142-9612(23)00432-5. [Epub ahead of print]304 122424

Glucosylation endows nanoparticles with TLR4 agonist capability to trigger macrophage polarization and augment antitumor immunity.

Li Liu, Shengxiang Fu, Wencheng Zhu, Zhongyuan Cai, Yingzi Cao, Yubing Huang, Li Yang, Xiaomin Fu, Rongrong Jin, Chunchao Xia, Yunjiao Zhang, Su Lui, Qiyong Gong, Bin Song, Longping Wen, James M Anderson, Hua Ai.

  Carbohydrates have emerged as promising candidates for immunomodulation, however, how to present them to immune cells and achieve potent immunostimulatory efficacy remains challenging. Here, we proposed and established an effective way of designing unique glyconanoparticles that can amplify macrophage-mediated immune responses through structural mimicry and multiple stimulation. We demonstrate that surface modification with glucose can greatly augment the immunostimulatory efficacy of nanoparticles, comparing to mannose and galactose. In vitro studies show that glucosylation improved the pro-inflammatory efficacy of iron oxide nanoparticles (IONPs) by up to 300-fold, with the immunostimulatory activity of glucosylated IONPs even surpassing that of LPS under certain conditions. In vivo investigation show that glucosylated IONPs elicited increased antitumor immunity and achieved favorable therapeutic outcomes in multiple murine tumor models. Mechanistically, we proposed that glucosylation potentiated the immunostimulatory effect of IONPs by amplifying toll-like receptors 4 (TLR4) activation. Specifically, glucosylated IONPs directly interacted with the TLR4-MD2 complex, resulting in M1 macrophage polarization and enhanced antitumor immunity via activation of NF-κB, MAPK, and STAT1 signaling pathways. Our work provides a simple modification strategy to endow nanoparticles with potent TLR4 agonist effects, which may shed new light on the development of artificial immune modulators for cancer immunotherapy.

Keywords:  Glucosylation; Iron oxide nanoparticles; Macrophage polarization; Toll-like receptors 4

DOI:  https://doi.org/10.1016/j.biomaterials.2023.122424
Dev Comp Immunol. 2023 Dec 16. pii: S0145-305X(23)01275-2. [Epub ahead of print]152 105122

Low-dose of formalin-inactivated Vibrio alginolyticus protects Crassostrea gigas from secondary infection and confers broad-spectrum Vibrio resistance on offspring.

Hebing Wang, Ben Yang, Qi Li, Shikai Liu.

  An increasing number of evidences have shown that invertebrate taxa can be primed to produce immune memory to resist the secondary infection of pathogens, which was considered as a viable option to protect invertebrates from pathogens. In this work, we compared the protective effect of several different immune priming methods on the Vibrio alginolyticus secondary infection of the Crassostrea gigas. The results showed that C. gigas primed with live V. alginolyticus had higher ROS level, which led to hemocytes necrosis and higher mortality rate in the later stage. Low-dose of formalin-inactivated V. alginolyticus (including 5 × 104 CFU/mL and 5 × 105 CFU/mL) elicited appropriate immune response in C. gigas, protecting C. gigas from V. alginolyticus infection. Immersion with 5 × 104 CFU/mL formalin-inactivated V. alginolyticus was performed to prime C. gigas immunity in the trans-generational immune priming. Trans-generational immune priming significantly increased the resistance of larvae to various Vibrio species. Overall, these results suggested that low-dose of formalin-inactivated V. alginolyticus can protect C. gigas from secondary infection and confer broad-spectrum Vibrio resistance on offspring. This work provided valuable information toward a new direction for the protection of C. gigas from Vibrio infection.

Keywords:  Crassostrea gigas; Immune priming; Trans-generational immune priming; Vibrio alginolyticus; Vibrio resistance

DOI:  https://doi.org/10.1016/j.dci.2023.105122
mBio. 2023 Dec 18. e0257123

Staphylococcus aureus suppresses the pentose phosphate pathway in human neutrophils via the adenosine receptor A2aR to enhance intracellular survival.

Emilio G Vozza, Clíodhna M Daly, Sinead A O'Rourke, Hannah K Fitzgerald, Aisling Dunne, Rachel M McLoughlin.

   IMPORTANCE: Staphylococcus aureus is one of the leading causes of antimicrobial-resistant infections whose success as a pathogen is facilitated by its massive array of immune evasion tactics, including intracellular survival within critical immune cells such as neutrophils, the immune system's first line of defense. In this study, we describe a novel pathway by which intracellular S. aureus can suppress the antimicrobial capabilities of human neutrophils by using the anti-inflammatory adenosine receptor, adora2a (A2aR). We show that signaling through A2aR suppresses the pentose phosphate pathway, a metabolic pathway used to fuel the antimicrobial NADPH oxidase complex that generates reactive oxygen species (ROS). As such, neutrophils show enhanced ROS production and reduced intracellular S. aureus when treated with an A2aR inhibitor. Taken together, we identify A2aR as a potential therapeutic target for combatting intracellular S. aureus infection.

Keywords:  A2aR; Staphylococcus aureus; adora2a; host-pathogen interactions; intracellular pathogen; metabolism; neutrophil; pentose phosphate pathway

DOI:  https://doi.org/10.1128/mbio.02571-23
Proc Natl Acad Sci U S A. 2023 Dec 26. 120(52): e2308853120

Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.

Fei Qin, Baoshan Cai, Runyu Cao, Xuemei Bai, Jiahua Yuan, Yuling Zhang, Yaxing Liu, Tian Chen, Feng Liu, Wanwei Sun, Yi Zheng, Xiaopeng Qi, Wei Zhao, Bingyu Liu, Chengjiang Gao.

  The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.

Keywords:  ALS; ESCRT; antiviral innate immunity; cGAS; listerin

DOI:  https://doi.org/10.1073/pnas.2308853120
Int Immunopharmacol. 2023 Dec 21. pii: S1567-5769(23)01744-7. [Epub ahead of print]127 111417

Saa3 promotes pro-inflammatory macrophage differentiation and contributes to sepsis-induced AKI.

Yi Peng, Yan Fang, Zhilan Li, Chenxi Liu, Weiru Zhang.

  Sepsis-induced acute kidney injury (SAKI) is a life-threatening condition with complex pathophysiology, often exacerbated by immune cell dysregulation. In this comprehensive study, we leverage publicly available single-cell RNA sequencing (scRNA-seq) datasets to unravel the intricate immune responses occurring during SAKI, shedding light on macrophages as critical players. Specifically, we identify Saa3, a gene primarily expressed in macrophages, as a potent pro-inflammatory cytokine in SAKI. Saa3hi Ccl2hi monocyte-derived infiltrated macrophages (IMs) emerge as a central effector subset, fostering inflammation, and directly engaging with renal cells. Our findings suggest that Saa3 may be a promising predictive marker of SAKI, although further exploration of human homologs is warranted.

Keywords:  Macrophage; Saa3; Sepsis-induced AKI; scRNA-seq

DOI:  https://doi.org/10.1016/j.intimp.2023.111417